The New Zealand rabbit is a species that is characteristically sensitive to dietary cholesterol and rapidly develops hypercholesterolemia and atherosclerosis. We have developed an unusual strain of this breed which is refractory to hypercholesterolemia. Our goal is to determine the mechanism(s) underlying the trait of cholesterol-unresponsiveness in this breed. Identifying the mechanism may provide indications acounting for intraspecies variability of cholesterol responsiveness know to occur in other species including man. Long-term objectives are to determine the genetic regulation of the mechanism, and assess roles that contributing factors to atherosclerotic disease, such as hypertension, have on genetic susceptibility. Specific aims are to determine: (a) exogenous cholesterol metabolism at major metabolic sites including dietary cholesterol absorption, intestinal transport of chylomicrons, compositional analysis of chylomicrons and chylomicron remnant particles, and bile acid synthesis, secretion and fecal excretion, and (b) endogenous metabolism including lipoprotein secretion from the liver, and hepatic and extrahepatic uptake, and catabolism in the cholesterol-unresponsive strain. The hypothesis is that the major mechanisms of unresponsivness are increased bile acid synthesis coupled with increased or unique receptor activity. The methodologies include: (a) radio-tracer sterol-bile acid balance studies using GLC-TLC-HPLC: (b) transport rates and compositional analysis of in vivo labeled chylomicrons, and remnant lipoproteins and apolipoproteins by centrifugation, PAGE, TLC, and GLC; (c) in vivo rates of bile acid synthesis (cholocystopexy), and fecal excretion; (d) hepatic lipoprotein-(apo) synthesis and secretion by liver perfusion, (e) labeled lipoprotein clearance rates (hepatic and extrahepatic); (f) fibroblast receptor characterization and cholesterol metabolism using culture- receptor techniques; and (g) measurements of HMA-CoA reductase and ACAT activity. Normal rabbits will be used as controls throughout the studies. Together these studies will identify the mechanism that accounts for the differential repsonse between the cholesterol-unresponsive and typical, responsive rabbit.